The ultimate goal of this project is to utilize knowledge of the physiology and pathophysiology of pain to develop novel techniques for controlling pain. The current focus of this project is the regulation of the N-methyl-D-aspartate (NMDA) subclass of excitatory amino acid receptors by the endogenous opioid peptide dynorphin. Dynorphin concentrations in the spinal cord increase as a result of persistent peripheral pain. This suggests that dynorphin may either suppress ongoing pain or may be partially responsible for the hyperalgesia or central sensitization that occurs during persistent pain. It is also well documented that opioids are capable of regulating the function of NMDA receptors. In the hippocampus, dynorphin can enhance NMDA receptors. In the hippocampus, dynorphin can enhance NMDA receptor activity through a non-opioid site and inhibit NMDA receptor activity through a site known as the Kappa2 opioid receptor. Dynorphin's role in the spinal cord during persistent pain is currently not known. Thus, the two specific aims of this study are to 1) determine if endogenous dynorphin suppresses persistent pain in the spinal cord by inhibiting NMDA receptors and 2) determine if dynorphin's non-opioid excitatory effects on NMDA receptors mediate some of the pathology associated with persistent pain. With this knowledge in hand, it is likely that novel strategies can be devised to control persistent pain.